1. Field of the Invention
The present invention relates to substituted indole-3-carbinol and diindolylmethane compounds and pharmaceutical compositions. The present invention also relates to the use of substituted indole-3-carbinol and diindolylmethane compositions in treating estrogen dependent tumors.
2. Description of the Prior Art
Breast cancer is one of the leading causes of premature death in North American women, and the formation and growth of both breast and endometrial tumors are estrogen-dependant. Mammary cancer is a complex disease process in which treatment with antiestrogens (endocrine therapy) or antineoplastic drugs depends on a number of factor including levels of estrogen receptor (ER) expression. The development of rational treatment strategies for mammary cancer is dependent on understanding regulation of mammary cancer development and growth and inhibition of these responses.
There is considerable evidence showing that steroid hormones are involved in development of some tumors, and treatment of these tumors has utilized strategies that modulate endocrine response pathways. For example, estrogens play a role in development and growth of mammary tumors in human and animal models, and various antiestrogens are utilized as endocrine therapies for treatment of this disease (Lerner L. J., et al., Cancer Res. 50:4177-4189, 1990). Antiestrogens are a class of chemicals which inhibit estrogens from eliciting their full response in target tissues. They can be used to explore the mechanisms of action of estrogens and to provide treatment for estrogen-dependent diseases (e g., tumors). An antiestrogenic compound currently being utilized in the treatment of mammary cancer is tamoxifen. Progesterone and related progestins have also been used extensively to treat mammary cancer in laboratory animals and humans. Numerous other antiestrogens have been disclosed in recent years including inhibitors of aromatase (Bednarski U.S. Pat. No. 4,745,109), antiestrogenic hydrazones (Morgan U.S. Pat. No. 4,732,904) and antiestrogenic benzothiophenes (Jones U.S. Pat. No. 4,418,068). Several studies have indicated that diet can influence the process of carcinogenesis, and both fruit and vegetables are reported to possess antimutagenic and anticarcinogenic properties in human, animal and cell models (Aldercreutz, Envir. Health Persp. 103(57) 103-112,1995). Cruciferous vegetables including broccoli, cauliflower, Brussels sprouts, and cabbage contain several compounds such as indoles, isothiocyanates and dithiolthiones which modulate carcinogenesis in different animal models. For example, glucobrassicin (3-indolymethyl glucosinolate), a major component of cauliflower (0.1 to 1.6 mmol/kg), cabbage (0.1 to 1.9 mmol/kg), and Brussels sprouts (0.5 to 3.2 mmol/kg), is readily converted to indole 3-carbinol (I3C). I3C and related compounds inhibit formation or growth of estrogen-regulated tumors in the rodent mammary, endometrium and uterus, suggesting that this compound may be acting as an antiestrogen. Wattenberg and Loub (Wattenberg L. W., et al., Cancer Res. 38:1410-1413, 1978) first showed that oral administration of I3C and its dimerization product, 3,3'diindolylmethane (DIM), 20 hours prior to treatment with DMBA, inhibited the occurrence of mammary tumors in female Sprague-Dawley rats, and dietary administration of Brussels sprouts also provided some protective effects. Several studies have reported that I3C inhibits mammary carcinogenesis in rodent models, thus exhibiting antiestrogenic activity (Kojima T. et al, Cancer Res. 54:1446-1449, 1994; Grubbs C. J. et al, Anticancer Res. 15:709-716, 1995). Dietary I3C and 20% Brussels sprouts inhibited DMBA-induced mammary tumor formation and progression (Stoewsand G. S. et al, Cancer Lett. 39:199-207, 1988). A recent study evaluated the effects of I3C on both DMBA- and methylnitrosourea (MNU)-induced mammary tumors in female Sprague-Dawley rats using several different treatment protocols (Grubbs C. J. et al, Anticancer Res. 15:709-716, 1995). However, none of these investigations have shown the utility of substituted I3C and DIM as antiestrogenic agents.
These and other advantages of the present invention will become apparent from the following detailed description.